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Research ArticleArticle

Substrate-Dependent Functional Alterations of Seven CYP2C9 Variants Found in Japanese Subjects

Keiko Maekawa, Noriko Harakawa, Emiko Sugiyama, Masahiro Tohkin, Su-Ryang Kim, Nahoko Kaniwa, Noriko Katori, Ryuichi Hasegawa, Kazuki Yasuda, Kei Kamide, Toshiyuki Miyata, Yoshiro Saito and Jun-ichi Sawada
Drug Metabolism and Disposition September 2009, 37 (9) 1895-1903; DOI: https://doi.org/10.1124/dmd.109.027003
Keiko Maekawa
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Noriko Harakawa
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Emiko Sugiyama
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Masahiro Tohkin
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Su-Ryang Kim
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Nahoko Kaniwa
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Noriko Katori
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Ryuichi Hasegawa
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Kazuki Yasuda
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Kei Kamide
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Toshiyuki Miyata
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Yoshiro Saito
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Jun-ichi Sawada
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Abstract

CYP2C9 is a polymorphic enzyme that metabolizes a number of clinically important drugs. In this study, catalytic activities of seven alleles found in Japanese individuals, CYP2C9*3 (I359L), *13 (L90P), *26 (T130R), *28 (Q214L), *30 (A477T), *33 (R132Q), and *34 (R335Q), were assessed using three substrates (diclofenac, losartan, and glimepiride). When expressed in a baculovirus-insect cell system, the holo and total (apo and holo) CYP2C9 protein expression levels were similar among the wild type (CYP2C9.1) and six variants except for CYP2C9.13. A large part of CYP2C9.13 was present in the apo form P420. Compared with CYP2C9.1, all variants except for CYP2C9.34 exhibited substrate-dependent changes in Km, Vmax, and intrinsic clearance (Vmax/Km). For diclofenac 4′-hydroxylation, the intrinsic clearance was decreased markedly (by >80%) in CYP2C9.13, CYP2C9.30, and CYP2C9.33 and variably (63–76%) in CYP2C9.3, CYP2C9.26, and CYP2C9.28 due to increased Km and/or decreased Vmax values. For losartan oxidation, CYP2C9.13 and CYP2C9.28 showed 2.5- and 1.8-fold higher Km values, respectively, and all variants except for CYP2C9.34 showed >77% lower Vmax and intrinsic clearance values. For glimepiride hydroxylation, the Km of CYP2C9.13 was increased 7-fold, and the Vmax values of all variants significantly decreased, resulting in reductions in the intrinsic clearance by >80% in CYP2C9.3, CYP2C9.13, CYP2C9.26, and CYP2C9.33 and by 56 to 75% in CYP2C9.28 and CYP2C9.30. These findings suggest the necessity for careful administration of losartan and glimepiride to patients bearing these six alleles.

Footnotes

  • This study was supported in part by the Program for the Promotion of Fundamental Studies in Health Sciences from the National Institute of Biomedical Innovation; and by the Health and Labor Sciences Research Grants from the Ministry of Health, Labor and Welfare.

  • Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.

  • doi:10.1124/dmd.109.027003.

  • ABBREVIATIONS: P450, cytochrome P450; OR, NADPH P450 reductase; ANOVA, analysis of variance; SRS, substrate recognition site.

    • Accepted June 15, 2009.
    • Received February 4, 2009.
  • The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 37 (9)
Drug Metabolism and Disposition
Vol. 37, Issue 9
1 Sep 2009
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Research ArticleArticle

Substrate-Dependent Functional Alterations of Seven CYP2C9 Variants Found in Japanese Subjects

Keiko Maekawa, Noriko Harakawa, Emiko Sugiyama, Masahiro Tohkin, Su-Ryang Kim, Nahoko Kaniwa, Noriko Katori, Ryuichi Hasegawa, Kazuki Yasuda, Kei Kamide, Toshiyuki Miyata, Yoshiro Saito and Jun-ichi Sawada
Drug Metabolism and Disposition September 1, 2009, 37 (9) 1895-1903; DOI: https://doi.org/10.1124/dmd.109.027003

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Research ArticleArticle

Substrate-Dependent Functional Alterations of Seven CYP2C9 Variants Found in Japanese Subjects

Keiko Maekawa, Noriko Harakawa, Emiko Sugiyama, Masahiro Tohkin, Su-Ryang Kim, Nahoko Kaniwa, Noriko Katori, Ryuichi Hasegawa, Kazuki Yasuda, Kei Kamide, Toshiyuki Miyata, Yoshiro Saito and Jun-ichi Sawada
Drug Metabolism and Disposition September 1, 2009, 37 (9) 1895-1903; DOI: https://doi.org/10.1124/dmd.109.027003
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